The present inventors previously found that a group of penem compounds represented by the following formula: ##STR2## wherein R.sub.1 is a hydrogen atom or allyl group,
--A-- represents an oxygen or methylene group, and PA1 --B-- represents a methylene, ethylene or carbonyl group, PA1 R.sub.3 represents a hydrogen or alkali metal atom or an amino residuum, and PA1 R has the same meaning as defined above.
and their salts have excellent antibacterial activities on both gram-positive and gram-negative, aerobic or anaerobic bacteria (Japanese Patent Publication No. 207387/1986).
High safety of these compounds has been confirmed by safety test in which laboratory animals were used. Their development as medical drugs is now expected.
In the meantime, it has been found by the study on the correlation between structure and, antibacterial activities of these compounds [J. Antibiotics, 41, 1685 (1988)] that, among 2-substituents of penem, (R)-2-tetrahydrofuryl group provides the highest antibacterial activities while (S)-2-tetrahydrofuryl group, a diastereomer at its 2-side chain group, and (R) or (S)-3-tetrahydrofuryl group, a position isomer, provide weaker activities particularly against gram-negative bacteria.
For these reasons, compounds represented by the following formula (II): ##STR3## wherein R2 represents a hydrogen atom or a group capable of forming a pharmaceutically-acceptable salt,
have drawn interest as antibiotics. These compounds are also interested in that they do not require any special chemical modification for oral absorption and they themselves can be developed as both injections and oral drugs.
Namely, the bioavailability of the above-described compounds per se in laboratory animal (rats) has been found by no means inferior to commercial drugs which are used clinically.
However, from the viewpoint of safety and economy further enhancement of their bioavailability upon oral administration is apparently more advantageous. As far as the above compounds are concerned, there is still a room for further improvement in this regard.
Regarding improvements in the absorption upon oral administration, extensive studies have been conducted on penicillin and cephalosporin antibiotics so that many of these antibiotics are used as curative medicines. There are, however, only a few study reports of this type on penem and carbapenem antibiotics [J. Antibiotics, 36, 983, (1983); Japanese Patent Laid-Open No. 6728/1990]. It has therefore been interested in determining whether or not the approaches used for penicillin and cephalosporin antibiotics are equally applicable to penem compounds.